Incidence of clinically significant bacteraemia in children who present to hospital in Kenya: community-based observational study.
Estimates of the burden of invasive bacterial disease in sub-Saharan Africa have previously relied on selected groups of patients, such as inpatients; they are, therefore, probably underestimated, potentially hampering vaccine implementation. Our aim was to assess the incidence of bacteraemia in all children presenting to a hospital in Kenya, irrespective of clinical presentation or decision to admit. We did a community-based observational study for which we cultured blood from 1093 children who visited a Kenyan hospital outpatient department. We estimated bacteraemia incidence with a Demographic Surveillance System, and investigated the clinical significance of bacteraemia and the capacity of clinical signs to identify cases. The yearly incidence of bacteraemia per 100,000 children aged younger than 2 years and younger than 5 years was 2440 (95% CI 1307-3573) and 1192 (692-1693), respectively. Incidence of pneumococcal bacteraemia was 597 (416-778) per 100,000 person-years of observation in children younger than age 5 years. Three-quarters of episodes had a clinical focus or required admission, or both; one in six was fatal. After exclusion of children with occult bacteraemia, the incidence of clinically significant bacteraemia per 100,000 children younger than age 2 years or 5 years fell to 1741 (790-2692) and 909 (475-1343), respectively, and the yearly incidence of clinically significant pneumococcal bacteraemia was 436 (132-739) per 100,000 children younger than 5 years old. Clinical signs identified bacteraemia poorly. Clinically significant bacteraemia in children in Kilifi is twice as common, and pneumococcal bacteraemia four times as common, as previously estimated. Our data support the introduction of pneumococcal vaccine in sub-Saharan Africa.


Stereochemistry of eudesmane cation formation during catalysis by aristolochene synthase from Penicillium roqueforti.
The aristolochene synthase catalysed cyclisation of farnesyl diphosphate (1) has been postulated to proceed through (S)-germacrene A (3). However, the active site acid that reprotonates this neutral intermediate has so far proved difficult to identify and, based on high level ab initio molecular orbital and density functional theory calculations, a proton transfer mechanism has recently been proposed, in which proton transfer from C12 of germacryl cation to the C6,C7-double bond of germacryl cation (2) proceeds either directly or via a tightly bound water molecule. In this work, the stereochemistry of the elimination and protonation reactions was investigated by the analysis of the reaction products from incubation of 1 and of [12,12,12,13,13,13-(2)H(6)]-farnesyl diphosphate (15) with aristolochene synthase from Penicillium roqueforti (PR-AS) in H(2)O and D(2)O. The results reveal proton loss from C12 during the reaction and incorporation of another proton from the solvent. Incubation of with PR-AS in D(2)O led to the production of (6R)-[6-(2)H] aristolochene, indicating that protonation occurs from the face of the 10-membered germacrene ring opposite the isopropylidene group. Hence these results firmly exclude proton transfer from C12 to C6 of germacryl cation. We propose here Lys 206 as the general acid/base during PR-AS catalysis. This residue is part of a conserved network of hydrogen bonds, along which protons could be delivered from the solvent to the active site.


Seminal Plasma Exposures Strengthen Vaccine Responses in the Female Reproductive Tract Mucosae.
HIV-1 sexual transmission occurs mainly via mucosal semen exposures. In the female reproductive tract (FRT), seminal plasma (SP) induces physiological modifications, including inflammation. An effective HIV-1 vaccine should elicit mucosal immunity, however, modifications of vaccine responses by the local environment remain to be characterized. Using a modified vaccinia virus Ankara (MVA) as a vaccine model, we characterized the impact of HIV-1+ SP intravaginal exposure on the local immune responses of non-human primates. Multiple HIV-1+ SP exposures did not impact the anti-MVA antibody responses. However, SP exposures revealed an anti-MVA responses mediated by CD4+ T cells, which was not observed in the control group. Furthermore, the frequency and the quality of specific anti-MVA CD8+ T cell responses increased in the FRT exposed to SP. Multi-parameter approaches clearly identified the cervix as the most impacted compartment in the FRT. SP exposures induced a local cell recruitment of antigen presenting cells, especially CD11c+ cells, and CD8+ T cell recruitment in the FRT draining lymph nodes. CD11c+ cell recruitment was associated with upregulation of inflammation-related gene expression after SP exposures in the cervix. We thus highlight the fact that physiological conditions, such as SP exposures, should be taken into consideration to test and to improve vaccine efficacy against HIV-1 and other sexually transmitted infections.


10-year outcome study of an early intervention program for psychosis compared with standard care service.
Despite evidence on the short-term benefits of early intervention (EI) service for psychosis, long-term outcome studies are limited by inconsistent results. This study examined the 10-year outcomes of patients with first-episode psychosis who received 2-year territory-wide EI service compared to those who received standard care (SC) in Hong Kong using an historical control design. Consecutive patients who received the EI service between 1 July 2001 and 30 June 2002, and with diagnosis of schizophrenia-spectrum disorders, were identified and matched with patients who received SC first presented to the public psychiatric service from 1 July 2000 to 30 June 2001. In total, 148 matched pairs of patients were identified. Cross-sectional information on symptomatology and functioning was obtained through semi-structured interview; longitudinal information on hospitalization, functioning, suicide attempts, mortality and relapse over 10 years was obtained from clinical database. There were 70.3% (N = 104) of SC and 74.3% (N = 110) of EI patients interviewed. Results suggested that EI patients had reduced suicide rate (χ2 (1) = 4.35, p = 0.037), fewer number [odds ratio (OR) 1.56, χ2 = 15.64, p < 0.0001] and shorter duration of hospitalization (OR 1.29, χ2 = 4.06, p = 0.04), longer employment periods (OR -0.28, χ2 = 14.64, p < 0.0001) and fewer suicide attempts (χ2 = 11.47, df = 1, p = 0.001) over 10 years. At 10 years, no difference was found in psychotic symptoms, symptomatic remission and functional recovery. The short-term benefits of the EI service on number of hospitalizations and employment was sustained after service termination, but the differences narrowed down. This suggests the need to evaluate the optimal duration of the EI service.


Volar locking plates versus K-wire fixation of dorsally displaced distal radius fractures--a functional outcome study.
Fractures of the distal radius are common. As the population of the western world ages, their incidence is set to increase further. There are various methods of treating these fractures, but optimal management remains controversial. In the United Kingdom, the most common surgical treatment of closed distal radius fractures is by Kirschner-wires (K-wires) or volar locking plate. In this study, we compared long-term functional outcomes of volar locking plates with those of K-wires. A retrospective comparative study of 71 patients with dorsally displaced distal radius fractures treated contemporaneously in two independent hospitals was performed. One group was treated with a volar locking plate (n = 36) and the other group with manipulation and K-wire fixation (n = 35). There was no difference between the two groups in terms of demographics or grade of fracture. Outcome was measured 15 months to 27 months post surgery using the Disabilities of the Arm, Shoulder and Hand score and the Patient-Rated Wrist Evaluation score. We found no statistical difference between the two groups in the Patient-Rated Wrist Evaluation score or Disabilities of the Arm, Shoulder and Hand score at 1 year to 2 years postsurgery. We have been unable to demonstrate a clinically relevant advantage of using volar locking plates over K-wires at 1 year to 2 years postoperatively.


Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure.
Recent studies demonstrate that mechanisms underlying gut barrier failure include systemic processes and less studied luminal processes. We thus tested the hypothesis that mucus layer oxidation is a component of trauma/hemorrhagic shock-induced gut injury and dysfunction. Male Sprague-Dawley rats underwent trauma/hemorrhagic shock. Controls underwent trauma only. Mucus from the terminal 30 cm of the ileum was collected, processed, and analyzed for reactive nitrogen intermediates (RNI)-mediated damage, reactive oxygen species (ROS)-induced damage, and total antioxidant capacity. The distal ileum was stained to quantify the mucus layer; gut permeability was assessed physiologically. A time course study was conducted to determine the temporal sequence of mucus layer damage. The role of free radical-mediated damage to the gut barrier was investigated by the effect of the free radical scavenger dimethyl sulfoxide on trauma/hemorrhagic shock-induced changes on the mucus and on gut permeability. Trauma/hemorrhagic shock increased intestinal permeability, which was associated with evidence of loss of the unstirred mucus layer. These changes correlated with increased ROS- and RNI-mediated mucus damage and loss of mucus total antioxidant capacity. Based on the time course study, ROS-mediated mucus damage and loss of total antioxidant capacity were present immediately following shock, whereas RNI-mediated damage was delayed for 3 h. Dimethyl sulfoxide ameliorated gut barrier loss, ROS-mediated changes to the mucus layer, and loss of total antioxidant capacity. There was no change in RNI-induced changes to the mucus layer. These results support the hypothesis that trauma/hemorrhagic shock leads to mucus damage and gut dysfunction through the generation of free radical species.


Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction.
Two 14-epi-analogs of 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D(3)], 19-nor-14-epi-23-yne-1,25-(OH)2D3 (TX522) and 19-nor-14,20-bisepi-23-yne-1,25-(OH)2D3 (TX527), show enhanced antiproliferative (at least 10-fold) and markedly lower calcemic effects both in vitro and in vivo, compared with 1,25-(OH)2D3. This study aimed to evaluate their superagonistic effect at the level of interaction between the Vitamin D receptor (VDR) and coactivators. Mammalian two-hybrid assays with VP16-fused VDR and GAL4-DNA-binding-domain-fused steroid receptor coactivator 1 (SRC-1), transcriptional intermediary factor 2 (Tif2), or DRIP205 showed the 14-epi-analogs to be more potent inducers of VDR-coactivator interactions than 1,25-(OH)2D3 (up to 16- and 20-fold stronger induction of VDR-SRC-1 interaction for TX522 and TX527 at 10(-10) M). Similar assays in which metabolism of 1,25-(OH)2D3 was blocked with VID400, a selective inhibitor of the 1,25-(OH)2D3-metabolizing enzyme CYP24, showed that the enhanced potency of these analogs in establishing VDR-coactivator interactions can only partially be accounted for by their increased resistance to metabolic degradation. Crystallization of TX522 complexed to the ligand binding domain of the human VDR demonstrated that the epi-configuration of C14 caused the CD ring of the ligand to shift by 0.5 angstroms, thereby bringing the C12 atom into closer contact with Val300. Moreover, C22 of TX522 made an additional contact with the CD1 atom of Ile268 because of the rigidity of the triple bond-containing side chain. The position and conformation of the activation helix H12 of VDR was strictly maintained. In conclusion, this study provides deeper insight into the docking of TX522 in the LBP and shows that stronger VDR-coactivator interactions underlie the superagonistic activity of the two 14-epi-analogs.


Shift work and sickness absence at a Norwegian hospital: a longitudinal multilevel study.
Shift work is known to be related to several negative health consequences and sickness absence. Research results regarding the relationship between types of shift schedules and sickness absence and whether and how individual factors moderate this relationship, are mixed though. The present paper aims to provide more insight in these relationships. We used registry data from a large Norwegian hospital gathered for the years 2012-2016, for >14 000 employees. With random effects at the individual and unit levels, we analysed the relationship between shift schedule worked and sickness absence in the same year. The results showed increased risk of short-term sickness absence for two-shift and three-shift rotations, as well as fixed night shifts compared with fixed-day shifts. We also found an increased number of absence periods for two-shift rotations without nights and three-shift rotations. Results for long-term sickness absence were mixed, with increased odds for two-shift rotations without nights, but reduced odds for three-shift rotations. We found partial support for a moderating influence of age, gender and parental status. There is a clear relationship between working shifts and increased risk of short-term sickness absence. The relationship persists across gender, age group and parental status. The relationship between shift work and long-term sickness absence appears to be schedule and population specific. These findings may have implications for HR policies and the organisation of shift work in healthcare organisations.


Analytic expressions for the black-sky and white-sky albedos of the cosine lobe model.
The cosine lobe model is a bidirectional reflectance distribution function (BRDF) that is commonly used in computer graphics to model specular reflections. The model is both simple and physically plausible, but physical quantities such as albedo have not been related to the parameterization of the model. In this paper, analytic expressions for calculating the black-sky and white-sky albedos from the cosine lobe BRDF model with integer exponents will be derived, to the author's knowledge for the first time. These expressions for albedo can be used to place constraints on physics-based simulations of radiative transfer such as high-fidelity ray-tracing simulations.


Polarization rotation vector solitons in a graphene mode-locked fiber laser.
Polarization rotation vector solitons formed in a fiber laser passively mode locked with atomic layer graphene were experimentally investigated. It was found that different from the case of the polarization locked vector soliton formed in the laser, two extra sets of spectral sidebands always appear on the soliton spectrum of the polarization rotating vector solitons. We confirm that the new sets of spectral sidebands have the same formation mechanism as that of the Kelly sidebands.


Compensated speckle imaging: theory and experimental results.
Previous analyses have predicted that improved power-spectrum estimation results from application of speckle-imaging postprocessing to compensated astronomical images. We report the first results, to our knowledge, of compensated-speckle-imaging experiments, conducted at a compensated telescope operated by the U.S. Air Force, that confirm these predictions. The power-spectrum signal-to-noise ratio is used as the metric for evaluating the performance. We report the results of power-spectrum estimation for a single star and three binary stars, and we reconstruct images of the binary stars using the bispectrum method to obtain the Fourier phase of the object. Compensated and uncompensated results are compared. A previously derived expression that expresses the power-spectrum signal-to-noise ratio in terms of the compensated optical transfer function statistics and object parameters is verified by experimental data.


Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival.
Transient pulmonary neuroendocrine cell hyperplasia and non-neuroendocrine lung tumors develop in nitrosaminetreated hamsters, which we hypothesized might modulate epithelial cell phenotype by expressing gene(s) homologous to human chromosome 3p gene(s) deleted in small cell carcinoma of the lung (SCLC). We differentially screened a chromosome 3 library using nitrosamine-treated versus normal hamster lung cDNAs and identified hepatocyte growth factor-like/macrophage-stimulating protein (HGFL/MSP) in injured lung. HGFL/MSP mRNA is low to undetectable in human SCLC and carcinoid tumors, but the HGFL/MSP tyrosine kinase receptor, RON, is present and functional on many of these neuroendocrine tumors. In H835, a pulmonary carcinoid cell line, and H187, a SCLC cell line, HGFL/ MSP induced adhesion/flattening and apoptosis. Using viable cell counts to assess proliferation after 14 d of treatment with HGFL/MSP, there is growth inhibition of H835 but not H187. Nitrosamine-treated hamsters also demonstrate pulmonary neuroendocrine cell apoptosis in situ during the same time period as expression of the endogenous HGFL/ MSP gene, immediately preceding the spontaneous regression of neuroendocrine cell hyperplasia. These observations suggest that HGFL/MSP might regulate neuroendocrine cell survival during preneoplastic lung injury, which could influence the ultimate tumor cell phenotype.


Inhibitory activities of marine sulfated polysaccharides against SARS-CoV-2.
Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world at an unprecedented rate. In the present study, 4 marine sulfated polysaccharides were screened for their inhibitory activity against SARS-CoV-2, including sea cucumber sulfated polysaccharide (SCSP), fucoidan from brown algae, iota-carrageenan from red algae, and chondroitin sulfate C from sharks (CS). Of them, SCSP, fucoidan, and carrageenan showed significant antiviral activities at concentrations of 3.90-500 μg mL-1. SCSP exhibited the strongest inhibitory activity with IC50 of 9.10 μg mL-1. Furthermore, a test using pseudotype virus with S glycoprotein confirmed that SCSP could bind to the S glycoprotein to prevent SARS-CoV-2 host cell entry. The three antiviral polysaccharides could be employed to treat and prevent COVID-19.


Health survey of 167 pet rabbits (Oryctolagus cuniculus) in Finland.
Only a limited amount of information is available about health status of pet rabbits. The aim of this study was to obtain data about the health status of pet rabbits considered healthy by the owners in Finland. Physical examination and lateral abdominal and lateral skull radiography were performed on 167 pet rabbits of which 118 (70.7 per cent) had abnormal findings in at least one examination. The most common findings were acquired dental disease (n=67, 40.1 per cent), vertebral column deformities and degenerative lesions (n=52, 31.1 per cent), skin disorders (n=28, 16.8 per cent) and eye disorders (n=12, 7.2 per cent). Vertebral column angulating deformities were significantly more common in dwarf lop rabbits (P≤0.001). The prevalence of health disorders was significantly higher in rabbits over three years of age of which 51 (82.3 per cent) had findings in at least one examination (P<0.05). Rabbits as prey animals hide their illness, which cause difficulties to owners to recognise health problems. Because of the high prevalence of clinical and radiological findings in apparently healthy pet rabbits, regular physical examinations are advised, especially for animals over three years old.


Genetic population structure and demography of an apex predator, the tiger shark Galeocerdo cuvier.
Population genetics has been increasingly applied to study large sharks over the last decade. Whilst large shark species are often difficult to study with direct methods, improved knowledge is needed for both population management and conservation, especially for species vulnerable to anthropogenic and climatic impacts. The tiger shark, Galeocerdo cuvier, is an apex predator known to play important direct and indirect roles in tropical and subtropical marine ecosystems. While the global and Indo-West Pacific population genetic structure of this species has recently been investigated, questions remain over population structure and demographic history within the western Indian (WIO) and within the western Pacific Oceans (WPO). To address the knowledge gap in tiger shark regional population structures, the genetic diversity of 286 individuals sampled in seven localities was investigated using 27 microsatellite loci and three mitochondrial genes (CR,COI, and cytb). A weak genetic differentiation was observed between the WIO and the WPO, suggesting high genetic connectivity. This result agrees with previous studies and highlights the importance of the pelagic behavior of this species to ensure gene flow. Using approximate Bayesian computation to couple information from both nuclear and mitochondrial markers, evidence of a recent bottleneck in the Holocene (2,000-3,000 years ago) was found, which is the most probable cause for the low genetic diversity observed. A contemporary effective population size as low as 111 [43,369] was estimated during the bottleneck. Together, these results indicate low genetic diversity that may reflect a vulnerable population sensitive to regional pressures. Conservation measures are thus needed to protect a species that is classified as Near Threatened.


Spontaneous derotation of compensatory lumbar curve after thoracic fusion in adolescent idiopathic scoliosis.
Currently, excellent three-dimensional correction can be achieved with use of segmental pedicle screw fixation in adolescent idiopathic scoliosis (AIS). In the majority of patients with major thoracic curves, selective thoracic fusion (STF) may be considered to maximize motion segment of the unfused lumbar spine. This study aimed to investigate the extent of spontaneous derotation of the lumbar curve following STF. AIS patients who underwent STF using posterior pedicle screw fixation were retrospectively reviewed. Angle of vertebral rotation was defined as the difference between the axial rotation angles of the apical vertebra and S1 vertebra on axial CT images. Radiographic measurements included major thoracic curve, thoracolumbar/lumbar curve (preoperative and postoperative), and side-bending curve. The relationships between the axial rotation of the lumbar spine and radiographic measurements were also analyzed. Thirty patients (all females) were included. Preoperative thoracic Cobb measured 62.1±9°, which improved to 20.3±5° at 2 years postoperatively, resulting in 67% correction. Preoperative lumbar Cobb measured 38.0±9°, which spontaneously improved to 19.0±7°, indicating a 50% correction. Preoperatively, the axial rotation of apical lumbar vertebra was 10.2±5.5°, which changed to 7.0±4.8° (32% spontaneous correction). Comparing the correction between the axial rotation of the lumbar spine and other parameters, postoperative angle of axial rotation correlated well with preoperative (r=0.79) and postoperative (r=0.82) lumbar Cobb angle. Meanwhile, the improvement of axial rotation of the lumbar spine correlated with postoperative thoracic curve (r=-0.42), postoperative lumbar curve (r=-0.57), and thoracic apical translation change (r=0.43). In AIS patients with major thoracic curves, spontaneous axial derotation of the lumbar curves occurred with a mean correction rate of 32% after STF. A greater spontaneous derotation of the lumbar curve would be related to correction of the thoracic curve.


Recent trends in the management of combined pancreatoduodenal injuries.
In an effort to better characterize the natural history of pancreatoduodenal injuries, we present a review of clinical experiences in the treatment of combined traumatic pancreatoduodenal injuries, focusing on patients in extremis. Records of patients with abdominal trauma admitted to a level 1 trauma center from 1997 to 2001 were reviewed. Of 240 patients who sustained a pancreatic or duodenal injury, 33 had combined pancreatoduodenal injuries. Eighty-two per cent of the patients (27/33) in this series had penetrating injuries, 72 per cent (24) sustained gunshot wounds (GSW). Thirty-one patients were male, and the mean age was 33 years (range, 7-74). These patients presented with an average Injury Severity Score (ISS) of 22 +/- 12 and an average Glasgow Coma Score of 14 +/- 2. Overall length of stay was 39 +/- 59 days (range, 0-351 days). These 33 patients underwent a total of 57 laparotomies with an average of 1.7 operations per patient (range, 1 to 5 operations). Eighty-four per cent of the patients had an associated gastrointestinal injury and 45 per cent had a major vascular injury. Thirteen of the 33 (39%) patients presented in extremis, all 13 underwent an abbreviated laparotomy. The complication rate was 36 per cent, including fistula, abscess, pancreatitis, and organ dysfunction. There were 6 hospital deaths for a mortality rate of 18 per cent. Pancreatoduodenal injuries are associated with a variety of other serious injuries, which add to the overall complexity of these patients. Abbreviated laparotomy may be helpful when managing combined pancreatoduodenal injuries in patients who are in extremis.


The atom-cavity microscope: single atoms bound in orbit by single photons
The motion of individual cesium atoms trapped inside an optical resonator is revealed with the atom-cavity microscope (ACM). A single atom moving within the resonator generates large variations in the transmission of a weak probe laser, which are recorded in real time. An inversion algorithm then allows individual atom trajectories to be reconstructed from the record of cavity transmission and reveals single atoms bound in orbit by the mechanical forces associated with single photons. In these initial experiments, the ACM yields 2-micrometer spatial resolution in a 10-microsecond time interval. Over the duration of the observation, the sensitivity is near the standard quantum limit for sensing the motion of a cesium atom.


Factors in the emergence of infectious diseases.
"Emerging" infectious diseases can be defined as infections that have newly appeared in a population or have existed but are rapidly increasing in incidence or geographic range. Among recent examples are HIV/AIDS, hantavirus pulmonary syndrome, Lyme disease, and hemolytic uremic syndrome (a foodborne infection caused by certain strains of Escherichia coli). Specific factors precipitating disease emergence can be identified in virtually all cases. These include ecological, environmental, or demographic factors that place people at increased contact with a previously unfamiliar microbe or its natural host or promote dissemination. These factors are increasing in prevalence; this increase, together with the ongoing evolution of viral and microbial variants and selection for drug resistance, suggests that infections will continue to emerge and probably increase and emphasizes the urgent need for effective surveillance and control. Dr. David Satcher's article and this overview inaugurate Perspectives, a regular section in this journal intended to present and develop unifying concepts and strategies for considering emerging infections and their underlying factors. The editors welcome, as contributions to the Perspectives section, overviews, syntheses, and case studies that shed light on how and why infections emerge, and how they may be anticipated and prevented.


The course of the conduction system in dextrocardia.
This is a serial section examination of the conduction system of five hearts of various types of dextrocardia. In one case of dextroversion the conduction system was found to be normal. In one case of mirror-image dextrocardia the conduction system was normal but in the opposite spatial position. In one heart of mixed (discordant) dextrocardia, the sinoatrial node was in correct morphologic position. There were two atrioventricular nodes - a posterior node close to the coronary sinus and an anterior node in the roof of the morphologic right atrium. They formed two separate bundles which joined in the left ventricle to form a "sling". In two cases of presumptive mirror-image dextrocardia, with a common atrium in situs inversus according to the morphology of the atrial appendages, with common atrioventricular orifice (CAVO), the sinoatrial node was situated in wrong positions. Two atrioventricular nodes and bundles again formed a sling. There are various types of slings in discordant dextrocardia.


A model of spatial epidemic spread when individuals move within overlapping home ranges.
One of the central goals of mathematical epidemiology is to predict disease transmission patterns in populations. Two models are commonly used to predict spatial spread of a disease. The first is the distributed-contacts model, often described by a contact distribution among stationary individuals. The second is the distributed-infectives model, often described by the diffusion of infected individuals. However, neither approach is ideal when individuals move within home ranges. This paper presents a unified modeling hypothesis, called the restricted-movement model. We use this model to predict spatial spread in settings where infected individuals move within overlapping home ranges. Using mathematical and computational approaches, we show that our restricted-movement model has three limits: the distributed-contacts model, the distributed-infectives model, and a third, less studied advective distributed-infectives limit. We also calculate approximate upper bounds for the rates of an epidemic's spatial spread. Guidelines are suggested for determining which limit is most appropriate for a specific disease.


Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart.
We report the cDNA cloning and characterization of mouse GATA-4, a new member of the family of zinc finger transcription factors that bind a core GATA motif. GATA-4 cDNA was identified by screening a 6.5-day mouse embryo library with oligonucleotide probes corresponding to a highly conserved region of the finger domains. Like other proteins of the family, GATA-4 is approximately 50 kDa in size and contains two zinc finger domains of the form C-X-N-C-(X17)-C-N-X-C. Cotransfection assays in heterologous cells demonstrate that GATA-4 trans activates reporter constructs containing GATA promoter elements. Northern (RNA) analysis and in situ hybridization show that GATA-4 mRNA is expressed in the heart, intestinal epithelium, primitive endoderm, and gonads. Retinoic acid-induced differentiation of mouse F9 cells into visceral or parietal endoderm is accompanied by increased expression of GATA-4 mRNA and protein. In vitro differentiation of embryonic stem cells into embryoid bodies is also associated with increased GATA-4 expression. We conclude that GATA-4 is a tissue-specific, retinoic acid-inducible, and developmentally regulated transcription factor. On the basis of its tissue distribution, we speculate that GATA-4 plays a role in gene expression in the heart, intestinal epithelium, primitive endoderm, and gonads.


A Review and Survey of Neurosurgeon-Hospital Relationships: Evolution and Options.
As healthcare delivery shifts from fee-for-service, episodic care to pay for performance and population health, both hospitals and physicians are looking for new forms of integration. A number of regulations and restrictions govern physician relationships with hospitals. In this paper, we review the legal basis for such relationships and the options available. We also survey neurosurgeons and hospital executives to gain their perspective on the current situation and likely future. Two series of structured interviews were conducted with 10 neurosurgeons who work in a range of situations in diverse markets, and with Memorial Hermann Healthcare System senior executive leadership. Their responses form the basis for the subsequent discussion. Neurosurgeons can be independent, join a confederation such as an Independent Physician Association or another type of "clinically integrated" network, or be employed by a hospital, medical school, or physician group. With varying levels of integration comes the strength of size, management expertise, negotiating leverage, economies of scale, and possibly financial advantages, but with impact on autonomy and independence. Constructive alignment can lead to a win-win situation for both the individual physician and the organization, but options vary widely due to heterogeneous local conditions. This paper reviews possible relationships, moving along a spectrum from no financial integration to full integration. Concepts such as physician leasing, professional service agreements, "clinical integration," and employment are presented. This paper offers a practical reference that might be useful to a new graduate, independent neurosurgeon considering integration, or employed physicians considering alternatives.


Antigen presentation kinetics control T cell/dendritic cell interactions and follicular helper T cell generation in vivo.
The production of high affinity, class switched antibodies produced by B cells hinges on the effective differentiation of T follicular helper (Tfh) cells. Here we define conditions specifically enhancing Tfh differentiation and providing protection in a model of influenza infection. Tfh responses were associated with prolonged antigen presentation by dendritic cells (DCs), which maintained T cell/DC interactions into stage 3 (>72 hr) of activation. Blocking stage 3 interactions ablated Tfh generation, demonstrating a causal link between T cell-DC behaviour and functional outcomes. The current data therefore explain how duration of antigen presentation affects the dynamics of T cell-DC interactions and consequently determine Tfh cell differentiation in the developing immune response.


Heparin enhances active site-dependent binding of tissue-type plasminogen activator to endothelial cells.
Human umbilical vein endothelial cells (HUVEC) in culture express two classes of binding sites for tissue-type plasminogen activator (t-PA). The high-affinity binding site has been identified as PA inhibitor type 1 (PAI-1), which binds to the catalytic portion of the molecule, while the second site binds t-PA through an active-site independent domain. Because recombinant t-PA (rt-PA) is often administered concomitantly with heparin, we investigated the effects of heparin on rt-PA binding to HUVEC. Preincubation of HUVEC with heparin at 4 degrees C increased the binding of radiolabeled rt-PA in a time- and dose-dependent manner. One-half maximal increase in binding was observed within 10 minutes of heparin addition. When HUVEC were preincubated with optimal concentrations (5 U/mL) of heparin for 4 hours at 4 degrees C, a 2.5- +/- 0.2-fold increase in specific binding was observed (mean +/- SEM, n = 12, P less than .01). Other highly sulfated glycosaminoglycans and fucoidan (a sulfated polymer of fucose) stimulated rt-PA binding as well, whereas glycosaminoglycans with lower sulfate content than heparin did not. Several results suggested that heparin increased the binding of rt-PA to "cell-associated" PAI-1. First, only active-site-dependent binding was enhanced by heparin, whereas binding of active-site blocked rt-PA was not affected. Second, extracts from HUVEC preincubated with heparin contained increased amounts of rt-PA-PAI-1 complexes as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Third, antibodies to PAI-1 blocked the increased binding entirely. HUVEC preincubated with heparin also bound increased amounts of enzymatically active radiolabeled urokinase-type PAs. However, HUVEC preincubated with heparin did not express increased amounts of immunoreactive PAI-1. Therefore, heparin, at therapeutic concentrations, may enhance or stabilize the association of PAs with endothelial cell-associated PAI-1.


Population density and water balance influence the global occurrence of hepatitis E epidemics.
In developing countries, the waterborne transmission of hepatitis E virus (HEV), caused by HEV genotypes 1 (HEV-1) and 2 (HEV-2), leads to the onset of large recurrent outbreaks. HEV infections are of particular concern among pregnant women, due to very high mortality rates (up to 70%). Unfortunately, good understanding of the factors that trigger the occurrence of HEV epidemics is currently lacking; therefore, anticipating the onset of an outbreak is yet not possible. In order to map the geographical regions at higher risk of HEV epidemics and the conditions most favorable for the transmission of the virus, we compiled a dataset of HEV waterborne outbreaks and used it to obtain models of geographical suitability for HEV across the planet. The main three variables that best predict the geographical distribution of HEV outbreaks at global scale are population density, annual potential evapotranspiration and precipitation seasonality. At a regional scale, the temporal occurrence of HEV outbreaks in the Ganges watershed is negatively correlated with the discharge of the river (r = -0.77). Combined, our findings suggest that ultimately, population density and water balance are main parameters influencing the occurrence of HEV-1 and HEV-2 outbreaks. This study expands the current understanding of the combination of factors shaping the biogeography and seasonality of waterborne viral pathogens such as HEV-1 and HEV-2, and contributes to developing novel concepts for the prediction and control of human waterborne viruses in the near future.


Learned manipulation at unconstrained contacts does not transfer across hands.
Recent studies about sensorimotor control of the human hand have focused on how dexterous manipulation is learned and generalized. Here we address this question by testing the extent to which learned manipulation can be transferred when the contralateral hand is used and/or object orientation is reversed. We asked subjects to use a precision grip to lift a grip device with an asymmetrical mass distribution while minimizing object roll during lifting by generating a compensatory torque. Subjects were allowed to grasp anywhere on the object's vertical surfaces, and were therefore able to modulate both digit positions and forces. After every block of eight trials performed in one manipulation context (i.e., using the right hand and at a given object orientation), subjects had to lift the same object in the second context for one trial (transfer trial). Context changes were made by asking subjects to switch the hand used to lift the object and/or rotate the object 180° about a vertical axis. Therefore, three transfer conditions, hand switch (HS), object rotation (OR), and both hand switch and object rotation (HS+OR), were tested and compared with hand matched control groups who did not experience context changes. We found that subjects in all transfer conditions adapted digit positions across multiple transfer trials similar to the learning of control groups, regardless of different changes of contexts. Moreover, subjects in both HS and HS+OR group also adapted digit forces similar to the control group, suggesting independent learning of the left hand. In contrast, the OR group showed significant negative transfer of the compensatory torque due to an inability to adapt digit forces. Our results indicate that internal representations of dexterous manipulation tasks may be primarily built through the hand used for learning and cannot be transferred across hands.


Strong Fermi level pinning induces a high rectification ratio and negative differential resistance in hydrogen bonding bridged single cytidine pair junctions.
We propose a high performance single molecule rectifier by sandwiching a deoxycytidine base pair between gold electrodes. The conductance of the single base pair junction can be controlled by its protonation status, with ON/OFF ratios between the protonated (pCC) and deprotonated (CC) junctions of 3-5 orders of magnitude. In the conducting pCC state, we observed a high rectification ratio of two orders of magnitude at bias voltage values around 0.1 V. This rectification ratio surpasses most of the theoretical designs for single molecular rectifiers, while the low working voltage implies significant energy efficiency. Negative differential resistance (NDR) was also witnessed in the protonated state, with a peak to valley ratio of 24. Both the rectifying and NDR effects originate from strong Fermi level pinning effects. The electronic performance offers these single base pair junctions potential applications as a unimolecular rectifier or switch with an NDR effect. The current-voltage response is unique compared with those of the reported canonical A-T and G-C pairs, and provides the possibility to be used for i-motif DNA structure recognition or sequencing.


Protective Effects of Chrysin Against Drugs and Toxic Agents.
Polyphenolic compounds, especially flavonoids, are known as the most common chemical class of phytochemicals, which possess a multiple range of health-promoting effects. Flavonoids are ubiquitous in nature. They are also present in food, providing an essential link between diet and prevention of several diseases. Chrysin (CH), a natural flavonoid, was commonly found in propolis and honey and traditionally used in herbal medicine. A growing body of scientific evidence has shown that CH possesses protective effects against toxic agents in various animal tissues, including brain, heart, liver, kidney, and lung. This study found that CH may be effective in disease management induced by toxic agents. However, due to the lack of information on human, further studies are needed to determine the efficacy of CH as an antidote agent in human. The present article aimed to critically review the available literature data regarding the protective effects of CH against toxic agent-induced toxicities as well as its possible mechanisms.


A Systematic Review and Meta-analysis of Psychosocial Interventions to Reduce Drug and Sexual Blood Borne Virus Risk Behaviours Among People Who Inject Drugs.
Opiate substitution treatment and needle exchanges have reduced blood borne virus (BBV) transmission among people who inject drugs (PWID). Psychosocial interventions could further prevent BBV. A systematic review and meta-analysis examined whether psychosocial interventions (e.g. CBT, skills training) compared to control interventions reduced BBV risk behaviours among PWID. 32 and 24 randomized control trials (2000-May 2015 in MEDLINE, PsycINFO, CINAHL, Cochrane Collaboration and Clinical trials, with an update in MEDLINE to December 2016) were included in the review and meta-analysis respectively. Psychosocial interventions appear to reduce: sharing of needles/syringes compared to education/information (SMD -0.52; 95% CI -1.02 to -0.03; I2 = 10%; p = 0.04) or HIV testing/counselling (SMD -0.24; 95% CI -0.44 to -0.03; I2 = 0%; p = 0.02); sharing of other injecting paraphernalia (SMD -0.24; 95% CI -0.42 to -0.06; I2 = 0%; p < 0.01) and unprotected sex (SMD -0.44; 95% CI -0.86 to -0.01; I2 = 79%; p = 0.04) compared to interventions of a lesser time/intensity, however, moderate to high heterogeneity was reported. Such interventions could be included with other harm reduction approaches to prevent BBV transmission among PWID.


Synthetic LXR ligand inhibits the development of atherosclerosis in mice.
The nuclear receptors LXRalpha and LXRbeta have been implicated in the control of cholesterol and fatty acid metabolism in multiple cell types. Activation of these receptors stimulates cholesterol efflux in macrophages, promotes bile acid synthesis in liver, and inhibits intestinal cholesterol absorption, actions that would collectively be expected to reduce atherosclerotic risk. However, synthetic LXR ligands have also been shown to induce lipogenesis and hypertriglyceridemia in mice, raising questions as to the net effects of these compounds on the development of cardiovascular disease. We demonstrate here that the nonsteroidal LXR agonist GW3965 has potent antiatherogenic activity in two different murine models. In LDLR(-/-) mice, GW3965 reduced lesion area by 53% in males and 34% in females. A similar reduction of 47% was observed in male apoE(-/-) mice. Long-term (12-week) treatment with LXR agonist had differential effects on plasma lipid profiles in LDLR(-/-) and apoE(-/-) mice. GW3965 induced expression of ATP-binding cassettes A1 and G1 in modified low-density lipoprotein-loaded macrophages in vitro as well as in the aortas of hyperlipidemic mice, suggesting that direct actions of LXR ligands on vascular gene expression are likely to contribute to their antiatherogenic effects. These observations provide direct evidence for an atheroprotective effect of LXR agonists and support their further evaluation as potential modulators of human cardiovascular disease.


Appraisals of Internal States and their Consequences: Relationship to Adolescent Analogue Bipolar Symptoms.
Extreme appraisals of internal states correlate with and prospectively predict mood symptoms in adults, and discriminate individuals with bipolar disorder from individuals with unipolar depression and non-clinical controls. These findings required replication in adolescents. This study sought to investigate the relationships between appraisals of internal states, mood symptoms and risk for bipolar disorder in an adolescent sample. A non-clinical sample (n = 98) of adolescents completed measures of mood symptoms, appraisals, and mania risk, alongside covariates. Appraisals of internal states were associated with analogue bipolar symptoms, independently of impulsivity and responses to positive affect. Positive appraisals of activated mood states were uniquely associated with hypomania, whilst negative appraisals were uniquely associated with depression and irritability symptoms. Individuals who appraised activated states as both extremely positive and extremely negative were more likely to score at high or moderate risk for future mania. This study is the first to demonstrate associations between appraisals of internal states, analogue mood symptoms and mania risk in adolescents. Clinical implications are discussed.


The eye: A window to the soul of the immune system.
The eye is considered as an immune privileged site, and with good reason. It has evolved a variety of molecular and cellular mechanisms that limit immune responses to preserve vision. For example, the cornea is mainly protected from autoimmunity by the lack of blood and lymphatic vessels, whereas the retina-blood barrier is maintained in an immunosuppressive state by the retinal pigment epithelium. However, there are several scenarios in which immune privilege is altered and the eye becomes susceptible to immune attack. In this review, we highlight the role of the immune system in two clinical conditions that affect the anterior and posterior segments of the eye: corneal transplantation and age-related macular degeneration. Interestingly, crosstalk between the innate and adaptive immune systems is critical in both acute and chronic inflammatory responses in the eye, with T cells playing a central role in combination with neutrophils and macrophages. In addition, we emphasize the advantage of using the eye as a model for in vivo longitudinal imaging of the immune system in action. Through this technique, it has been possible to identify functionally distinct intra-graft motility patterns of responding T cells, as well as the importance of chemokine signaling in situ for T cell activation. The detailed study of ocular autoimmunity could provide novel therapeutic strategies for blinding diseases while also providing more general information on acute versus chronic inflammation.


Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells.
Previously we have reported the purification and characterization of a novel cytokine from an EBV-transformed B cell line, RPMI 8866. This factor, termed natural killer cell stimulatory factor (NKSF), possessed pleiotropic activities including the induction of IFN-gamma from PBL, enhancement of cytotoxicity by NK cells, and stimulation of the proliferation of PBL. Purified NKSF was found to be a disulfide-linked heterodimeric protein composed of 35-kDa and 40-kDa subunits (p35 and p40). We now report the molecular cloning of cDNA for both subunits of NKSF from RPMI 8866 cellular RNA. The cDNA sequences indicate that both genes are novel, and Southern blot analysis confirmed that both cDNA are of human genomic origin. [35S]Methionine labeling indicated that cos-1 cells transfected with either p35 or p40 cDNA produced unique protein species of appropriate size. Methionine labeling of cos-1 cells cotransfected with p35 plus p40 cDNA yielded a broad band migrating between 70 and 90 kDa on a nonreducing gel. Reduction of this high molecular weight material yielded bands correlating with p35 and p40 gene products. Only culture supernatant from cotransfected cos-1 cells had a high level of NKSF biologic activity. That the high molecular weight material was responsible for this activity was indicated by the observation that biologic activity in the culture supernatant migrated at 70 to 90 kDa in a nonreducing gel. Furthermore, anti-p40 serum was able to block the biologic activities of both recombinant and natural NKSF, which indicates that it is a component of the active protein. In contrast, no activity could be detected in the supernatants of cos-1 cells transfected with p40 or p35 cDNA alone. The spectrum of biologic activity produced by cotransfected cos-1 cells was the same as NKSF purified to homogeneity from the RPMI 8866 cell line. A synergistic augmentation of some of these responses was found by the addition of IL-2 or the co-stimulators PHA or phorbol diester. The synergistic stimulation by NKSF plus IL-2 of T and NK function supports the possibility that these cytokines might prove useful in cancer therapy.


SU-E-T-609: Improving the Efficiency of VMAT Plan Optimization by Using Sparse Decomposition Method.
Volumetric modulated arc therapy (VMAT) is capable of delivering highly conformable dose distribution efficiently. Its planning is, however, more computationally intensive and requires a huge amount of memory space for optimization. We present an efficient sparse decomposition method for VMAT plan optimization. A quadratic objective function with volumetric constraints is expressed as a function of the aperture shapes and weights of the incident beams. The algorithm generates a sequence of iterates to solve the optimization problem. Each step of iteratively reweighed method is to be updated by solving the subproblem involving a quadratic (L2) term and a sparsity-inducing regulation (L1) term. Through the sparse decomposition techniques of the given problem, the deliverable apertures are directly generated. The shape of each aperture is iteratively rectified to be a sequencing of arc using the manufacture constraints. An initial arc spacing of 8 degree creates 45 beams directions for a single arc, 360 degree. The angular separation is equispaced every 2 degree over the end of optimization cycle. The optimization is implemented for a Varian TrueBeamTM STX linac beams with and without flattening filters available. Three clinical cases, head and neck, lung, and prostate, have been studied for the purpose of evaluating the planning efficiency and quality of the plans. The target dose coverage and critical structure sparing of VMAT plan are comparable to those of IMRT plans. The VMAT plan delivers lower doses to other OARs while keeping the similar target dose coverage to IMRT plan. The VMAT plan optimizations takes less than 3 minutes on average of the cases indicating great efficiency compared to existing methods. The results demonstrate that the proposed method provides competent computational efficiency for optimizing VMAT plan. The method substantially improves the speed and accuracy of VMAT plan optimization and makes future on-treatment adaptive re-planning possible.


Chronic treatment with long-acting nifedipine reduces vasoconstriction to endothelin-1 in essential hypertension.
Essential hypertension is associated with enhanced biological activity of endothelin-1 (ET-1) and impaired endothelium-dependent vasodilatation. Dihydropyridine calcium antagonists have antioxidant activity in vitro, and they improve endothelial function in vivo. We tested whether calcium antagonists also influence the biological activity of ET-1 in essential hypertensive (EH) patients in the presence and absence of hypercholesterolemia. In 9 healthy subjects (normotensive [NT] subjects, age: 48.3+/-7.6 years; blood pressure: 118+/-8.6/69+/-5.4 mm Hg) and 21 EH subjects (age: 50.0+/-7.8 years; blood pressure: 164.4+/-5.4/103.8+/-4.4 mm Hg), we studied forearm blood flow and its modification induced by intrabrachial administration of ET-1, phenylephrine, acetylcholine, and sodium nitroprusside at baseline and after 24 weeks of treatment with a nifedipine gastrointestinal therapeutic system (30 to 60 mg per day). At baseline, the first dose of ET-1 (0.5 microg/100 mL of forearm tissue per minute) caused a slight vasodilatation in NT but not in EH subjects, whereas the following higher doses caused a comparable dose-dependent vasoconstriction in EH and NT subjects. The effect of acetylcholine was significantly reduced in EH as compared with NT subjects. In contrast, sodium nitroprusside and phenylephrine had similar effects in NT and EH subjects. After chronic treatment with the nifedipine gastrointestinal therapeutic system, the vasoconstrictor effect induced by both ET-1 and phenylephrine was significantly blunted, whereas the response to acetylcholine was significantly increased and the vasodilation to sodium nitroprusside unchanged. Hypercholesterolemic EH subjects showed a further reduced response to acetylcholine compared with normocholesterolemic EH subjects, and the nifedipine gastrointestinal therapeutic system restored the vasodilation to acetylcholine in this subgroup. In conclusion, in EH subjects, chronic treatment with a long-acting dihydropyridine calcium antagonist not only exhibits a blood pressure-lowering effect but also reduces ET-1-induced vasoconstriction and improves endothelium-dependent vasodilation. Those vasculoprotective effects may importantly contribute to a reduction in major clinical events seen during treatment with these compounds.


Do GluN2B subunit containing NMDA receptors tolerate a fluorine atom in the phenylalkyl side chain?
The influence of an F-atom in the side chain of benzo[7]annulen-7-amines on the affinity towards GluN2B subunit containing NMDA receptors and the selectivity over related receptors was investigated. The synthesis of 5a and 5b was performed by reductive amination of the ketone 6 with primary alkanamines 14a and 14b bearing an F-atom in β-position. The GluN2B affinities of non-fluorinated and fluorinated ligands 4 and 5 are almost identical. The low impact of the F-atom on GluN2B affinity was unexpected, as it influences several chemical and physicochemical properties of the ligands. However, introduction of the F-atom led to reduced selectivity over σ receptors. Whereas 5a and 5b display still a 2-3-fold preference for GluN2B over σ1 receptors, they show almost the same affinity to GluN2B and σ2 receptors.


In situ hybridization analysis of the expression of human telomerase RNA in normal and pathologic conditions of the skin.
Human telomerase RNA (hTER) expression in skin was examined by in situ hybridization analysis. All newborn foreskins examined (n = 5) expressed hTER in epidermal basal cells at moderate levels. Telomerase RNA was not detectable in most adult specimens from sun protected areas (six of seven), whereas all samples obtained from sun exposed areas (n = 8) showed moderate hTER signals in epidermal basal cells. Telomerase RNA was also detected at moderate to strong levels in basal cells of psoriasis, contact dermatitis, and the proliferative cells of the anagen hair bulb. Basal cell carcinoma samples (14 of 15) had moderate to high hTER expression throughout the entire tumor, whereas squamous cell carcinomas (seven of eight) showed variable intensities of hTER expression but only in the cells at the periphery of tumor nests. All melanomas examined (n = 5) had moderate hTER expression in all tumor cells. The hTER signal intensities in skin tumors did not correlate with the age or sex of the donors, the clinical history of the lesions, or the histologic subtypes. To address whether hTER expression correlated with the proliferative state, sequential sections were stained with anti-Ki-67 antibody, a proliferation marker. In newborn foreskins, squamous cell carcinomas, and basal cell carcinomas, the distributions of hTER and Ki-67 were similar but not always identical. Telomerase RNA was more abundant than Ki-67 in the basal and suprabasal layer of newborn foreskins, suggesting that hTER expression is present both in actively cycling and in resting cells.


Practice and perspectives of Australian dietitians in management of patients on pancreatic enzyme replacement therapy.
Prescribing pathways for Australian dietitians are limited in comparison to dietitians practising in New Zealand and the United Kingdom. Therefore where medication dose may be titrated relative to dietary intake, such as in pancreatic exocrine insufficiency, dietitians in Australia are unable to initiate therapy or adjust dosage. To explore current practice roles of Australian dietitians working with patients requiring pancreatic enzyme replacement therapy (PERT), and opinions and influences on these practices. An online survey and telephone interviews with self-nominated dietitians who identified with extended scope of practice with patients on PERT. Thematic analysis was undertaken through an inductive approach to better understand the contexts and reasoning around a dietitian's extended scope of practice. The majority of participants in the online survey (74/81) described roles beyond traditional scope of practice with patients requiring PERT, especially in a multidisciplinary team environment. Most respondents (97%) believed PERT prescribing for dietitians would be beneficial. Nine semi-structured telephone interviews with experienced dietitians revealed perceived benefits of current advanced and informal extended scope of practice for dietitians including greater efficiency; improved patient care; increased job satisfaction and enhanced inter-professional communication. Dietitians believe they are adequately equipped to prescribe medication where dose is largely dependent upon diet. In Australia, it is common for dietitians in care of patients prescribed PERT to engage in informal, extended scope of practice. Further research is required to determine the framework to achieve formal extended scope of practice related to PERT and potentially other medications.


A multi-layer network approach to MEG connectivity analysis.
Recent years have shown the critical importance of inter-regional neural network connectivity in supporting healthy brain function. Such connectivity is measurable using neuroimaging techniques such as MEG, however the richness of the electrophysiological signal makes gaining a complete picture challenging. Specifically, connectivity can be calculated as statistical interdependencies between neural oscillations within a large range of different frequency bands. Further, connectivity can be computed between frequency bands. This pan-spectral network hierarchy likely helps to mediate simultaneous formation of multiple brain networks, which support ongoing task demand. However, to date it has been largely overlooked, with many electrophysiological functional connectivity studies treating individual frequency bands in isolation. Here, we combine oscillatory envelope based functional connectivity metrics with a multi-layer network framework in order to derive a more complete picture of connectivity within and between frequencies. We test this methodology using MEG data recorded during a visuomotor task, highlighting simultaneous and transient formation of motor networks in the beta band, visual networks in the gamma band and a beta to gamma interaction. Having tested our method, we use it to demonstrate differences in occipital alpha band connectivity in patients with schizophrenia compared to healthy controls. We further show that these connectivity differences are predictive of the severity of persistent symptoms of the disease, highlighting their clinical relevance. Our findings demonstrate the unique potential of MEG to characterise neural network formation and dissolution. Further, we add weight to the argument that dysconnectivity is a core feature of the neuropathology underlying schizophrenia.


Rescue of Advanced Pompe Disease in Mice with Hepatic Expression of Secretable Acid α-Glucosidase.
Pompe disease is a neuromuscular disorder caused by disease-associated variants in the gene encoding for the lysosomal enzyme acid α-glucosidase (GAA), which converts lysosomal glycogen to glucose. We previously reported full rescue of Pompe disease in symptomatic 4-month-old Gaa knockout (Gaa-/-) mice by adeno-associated virus (AAV) vector-mediated liver gene transfer of an engineered secretable form of GAA (secGAA). Here, we showed that hepatic expression of secGAA rescues the phenotype of 4-month-old Gaa-/- mice at vector doses at which the native form of GAA has little to no therapeutic effect. Based on these results, we then treated severely affected 9-month-old Gaa-/- mice with an AAV vector expressing secGAA and followed the animals for 9 months thereafter. AAV-treated Gaa-/- mice showed complete reversal of the Pompe phenotype, with rescue of glycogen accumulation in most tissues, including the central nervous system, and normalization of muscle strength. Transcriptomic profiling of skeletal muscle showed rescue of most altered pathways, including those involved in mitochondrial defects, a finding supported by structural and biochemical analyses, which also showed restoration of lysosomal function. Together, these results provide insight into the reversibility of advanced Pompe disease in the Gaa-/- mouse model via liver gene transfer of secGAA.


Antivenom therapy of carpet viper (Echis ocellatus) envenoming: effectiveness and strategies for delivery in West Africa.
In West Africa, response to specific, geographically appropriate, antivenom is often dramatic following carpet viper (Echis ocellatus) envenoming with rapid restoration of blood coagulability and resolution of spontaneous haemorrhage. Envenoming from Australasian snakes causing similar coagulopathies may respond less dramatically and the effectiveness of antivenom is being questioned. Here we have reviewed and re-analysed all published preclinical and clinical studies on envenoming and antivenom therapy conducted in West Africa to determine the effectiveness of antivenom. 22 studies provided relevant information: 12 observational studies, 4 RCTs and 6 preclinical studies. Four comparative studies confirmed statistically significant protection against mortality ranging from 57 to 87% using specific antivenoms compared to non-specific or no antivenoms. Meta-analysis estimated combined Odds Ratio (95% CI) of 0.25 (0.14-0.45) of dying among those treated with specific antivenom or 75% (95% CI: 55-86%) protection against death. Mortality more than doubled during times when stocks of reliable antivenoms ran out, with Relative Risk (95% CI)] of 2.33 (1.26-4.06). Serum kinetics of venom antigen/antivenom levels also confirmed that decline of venom antigen levels coincided with resolution of coagulopathy while decline of antivenom levels was associated with venom antigen reappearance and recurrence of coagulopathy. Preclinical and antivenomics analysis confirmed efficacy of regionally appropriate antivenoms against E. ocellatus and related species' venoms in Sub-Saharan Africa but not against Asian Echis carinatus venom. Antivenoms raised against E. carinatus were ineffective in human studies. In West Africa, specific antivenom is effective in managing carpet viper envenoming. A centralized hub-and-spoke strategy is suggested for broadening antivenom access to endemic rural areas together with instituting quality assurance, standardization and manpower training. Benefits, risks, cost-effectiveness and feasibility of the approach should be formally assessed.


The metabolic fate of stiripentol in man.
The metabolism of stiripentol (I), a new antiepileptic drug, was studied in healthy human subjects. Following a single 1200-mg oral dose to one subject, 13 metabolites of I were detected in urine and were identified by GC/MS techniques. The structures of 9 of these metabolites were confirmed subsequently by synthesis of the corresponding reference compounds. The nature of the urinary metabolites of I revealed the operation of five distinct metabolic pathways for this drug, viz. conjugation with glucuronic acid, oxidative cleavage of the methylenedioxy ring system, O-methylation of catechol metabolites, hydroxylation of the t-butyl group, and conversion of the allylic alcohol side-chain to the isomeric 3-pentanone structure. Metabolites of I excreted into urine over 12 hr accounted for the majority (73%) of an acute dose, whereas a further 18% was recovered in feces as the unchanged drug. These findings suggested that the search for additional metabolites would yield only trace amounts. From a quantitative standpoint, the most important pathway of biotransformation of I following both acute and chronic dosing involved opening of the methylenedioxy ring to generate catechol derivatives. This finding probably accounts for the known inhibitory effects of I on the oxidative metabolism of other antiepileptic agents and for the clinically significant drug interactions involving stiripentol.


Identification of tissue- and cancer-selective promoters for the introduction of genes into human ovarian cancer cells.
One potential limitation of gene therapy for epithelial tumors is the lack of tissue or tumor specificity of treatment. Tumor-selective expression of gene therapies may avoid deleterious side effects and improve the efficacy of the treatment. The aim of this study was to evaluate the tissue and tumor specificity of four different potential gene therapy promoters, to determine their usefulness in tissue-specific gene therapy of epithelial ovarian carcinomas. Three potential epithelial cell-selective (hESE1, SLP1, OSP1) and one potential tumor-selective (hTERT) promoter were placed upstream of a luciferase construct to determine relative activity in a wide variety of normal and malignant cell lines. Transient transfection and luciferase assays were carried out in 12 epithelial ovarian (3 SV40 T antigen-transfected normal and 9 malignant) and 8 control cell lines. Luciferase assays revealed that the hTERT promoter presented the highest tumor selectivity. hESE1 and SLP1 promoters showed strong epithelial cell selectivity (hESE1, 16/17; SLP1, 15/17), with the OSP1 (11/17) promoter exhibiting lower epithelial selectivity. Of the potential promoters for gene therapy, hTERT promoter exhibited the strongest transcriptional activity in most of the tumor cell lines. None of the promoters exhibited strict ovarian epithelium selectivity. The hTERT promoter may be an optimal promoter for a univector gene therapy approach based on its high tumor selectivity. Utilization of multiple epithelial cell-specific promoters may result in a more tissue-selective gene therapy approach. Using a combination of promoters may prevent potential problems due to expression in nonepithelial stem cells that may constitutively express hTERT.


Identifying attributes required by Foundation Year 1 doctors in multidisciplinary teams: a tool for performance evaluation.
Effective working in multidisciplinary teams (MDTs) is promoted as essential in ensuring good healthcare outcomes, suggesting that an understanding exists of the relationship between outcomes and the attributes needed by individuals to function effectively in the MDT. While the characteristics of effective teamwork have been described, the attributes needed by individual MDT members have not been investigated. To address this, the study focuses on newly qualified Foundation Year 1 (FY1) doctors, creating and testing a tool to evaluate their performance in the MDT. Repertory grid technique was used to elicit attributes needed by FY1 doctors to function effectively in the MDT. Study participants (all experienced MDT members) used these to evaluate MDT working by FY1 doctor colleagues. Data on 57 FY1 doctors were collected from 95 MDT members working in five hospitals. Participants also ranked the attributes in terms of importance for effective team functioning and rated an 'Ideal' FY1 doctor. The repertory grid permitted differentiation between groups of FY1 doctors' MDT performance. FY1 doctors who undertook interprofessional training were rated no differently than UK-trained graduates without such training. UK-trained graduates were rated significantly higher on all attributes than non-UK-trained graduates. Overall, FY1 doctors were rated lower than the 'Ideal'. Factor analysis and rankings suggested tensions between clinical attributes needed for good team functioning and more 'social' attributes. This study demonstrates the potential of repertory grid methodology in eliciting attributes that are important for effective teamworking, and using these to evaluate MDT working by FY1 doctors.


Factors affecting front line casualty care in Afghanistan.
Limited research has been undertaken to assess the effectiveness of pre-hospital care given at the point of wounding, nor how battlefield conditions affect the implementation of Battlefield Advanced Trauma Life Support (BATLS). This study examines the quality of care given at Role 1 and the psychological impact on clinical personnel of the application of current pre-hospital trauma management guidelines. Data was collected through 17 digitally recorded semi-structured interviews with healthcare clinicians deployed in Role 1 medical facilities on OP HERRICK 14 following major medical incidents. Interview transcripts were subjected to content analysis based on a modified grounded theory approach. Triage was found to be done poorly with individuals treating patients as they were found rather than by identifying clinical priorities. Pain management was not always achieved. Fluid replacement was hampered with difficulty in obtaining parenteral access. Subsequently fluids were sometimes given in excess of protocols. Clinical documentation was not always completed even after a patient had been evacuated. Some interesting elements were noted, such as post incident reports being used as a reflective process which may be self-developmental and help clinicians deal psychologically with the incident. Clinical personnel carry out their duties, irrespective of personal injury or threats to their safety. However their performance may be tapered under such stress. Human factors training prior to deployment may help to ensure adherence to BATLS protocols despite the complexities of the battle space. The data identified a number of factors that affected clinicians ability to provide a high standard of casualty care. The general perception of this research cohort was that despite all the obstacles, the level of trauma care was of a high nature. However, the study provides pointers to a number of areas for future exploration where patient care was not BATLS protocol compliant.


Spatiotemporal Patterns of High-Frequency Activity (80-170 Hz) in Long-Term Intracranial EEG.
To determine the utility of high-frequency activity (HFA) and epileptiform spikes as biomarkers for epilepsy, we examined the variability in their rates and locations using long-term ambulatory intracranial EEG (iEEG) recordings. This study used continuous iEEG recordings obtained over an average of 1.4 years from 15 patients with drug-resistant focal epilepsy. HFA was defined as 80- to 170-Hz events with amplitudes clearly larger than the background, which was automatically detected with a custom algorithm. The automatically detected HFA was compared with visually annotated high-frequency oscillations (HFOs). The variations of HFA rates were compared with spikes and seizures on patient-specific and electrode-specific bases. HFA included manually annotated HFOs and high-amplitude events occurring in the 80- to 170-Hz range without observable oscillatory behavior. HFA and spike rates had high amounts of intrapatient and interpatient variability. Rates of HFA and spikes had large variability after electrode implantation in most of the patients. Locations of HFA and spikes varied up to weeks in more than one-third of the patients. Both HFA and spike rates showed strong circadian rhythms in all patients, and some also showed multiday cycles. Furthermore, the circadian patterns of HFA and spike rates had patient-specific correlations with seizures, which tended to vary across electrodes. Analysis of HFA and epileptiform spikes should consider postimplantation variability. HFA and epileptiform spikes, like seizures, show circadian rhythms. However, the circadian profiles can vary spatially within patients, and their correlations to seizures are patient-specific.


High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome.
Habitual diet plays a major role in shaping the composition of the gut microbiota, and also determines the repertoire of microbial metabolites that can influence the host. The typical Western diet corresponds to that of an omnivore; however, the Mediterranean diet (MD), common in the Western Mediterranean culture, is to date a nutritionally recommended dietary pattern that includes high-level consumption of cereals, fruit, vegetables and legumes. To investigate the potential benefits of the MD in this cross-sectional survey, we assessed the gut microbiota and metabolome in a cohort of Italian individuals in relation to their habitual diets. We retrieved daily dietary information and assessed gut microbiota and metabolome in 153 individuals habitually following omnivore, vegetarian or vegan diets. The majority of vegan and vegetarian subjects and 30% of omnivore subjects had a high adherence to the MD. We were able to stratify individuals according to both diet type and adherence to the MD on the basis of their dietary patterns and associated microbiota. We detected significant associations between consumption of vegetable-based diets and increased levels of faecal short-chain fatty acids, Prevotella and some fibre-degrading Firmicutes, whose role in human gut warrants further research. Conversely, we detected higher urinary trimethylamine oxide levels in individuals with lower adherence to the MD. High-level consumption of plant foodstuffs consistent with an MD is associated with beneficial microbiome-related metabolomic profiles in subjects ostensibly consuming a Western diet. This study was registered at clinical trials.gov as NCT02118857.


Levels, Isomer Profiles, and Estimated Riverine Mass Discharges of Perfluoroalkyl Acids and Fluorinated Alternatives at the Mouths of Chinese Rivers.
An extensive sampling campaign was undertaken to study the levels, isomer profiles and riverine mass discharges of perfluoroalkyl acids (PFAAs) and fluorinated alternatives in 19 Chinese rivers. The levels and homologue profiles of Σ10PFAAs varied considerably among the 19 rivers (mean 106; median 16.3, range 8.9-1240 ng/L), indicating the influence of specific point sources. Highly branched isomer profiles of perfluorooctanoic acid (18-25% br-PFOA) in rivers with elevated concentrations (96-352 ng/L) indicate that releases during production of PFOA by electrochemical fluorination and/or its use in fluoropolymer manufacture were the dominant sources to these rivers. The fluorinated alternatives 6:2 fluorotelomer sulfonate (detection frequency 21%, < 0.1-3.1 ng/L) and chlorinated polyfluoroalkyl ether sulfonate F-53B (51%, < 0.56-78.5 ng/L) were also found in some rivers. The total Chinese riverine mass discharges of PFOA (mean 80.9; range 16.8-168 t/y) (including monitoring data from this and other studies) were in good agreement with theoretical PFOA emission estimates (17.3-203 t/y) whereas riverine mass discharges of PFOS (mean 3.6; range 1.9-5.6 t/y) could only account for a minor fraction of theoretically estimated PFOS releases (70 t/y). This study provides empirical evidence that emissions from Chinese point sources likely dominate the global emissions of several legacy PFASs (notably PFOA) and fluorinated alternatives (e.g., F-53B).


Circulating neutrophils in septic preterm neonates: comparison of two reference ranges.
To study the effect of sepsis on circulating neutrophils in very low birth weight neonates and to assess the usefulness of recently revised reference ranges for circulating neutrophils in the diagnosis of sepsis in this population by comparison with previously reported reference ranges. Neutrophil parameters (absolute total neutrophils, absolute total immature neutrophils, and the immature:total neutrophil proportion) were analyzed retrospectively in 202 sepsis episodes in 192 neonates (birth weight = 1055 +/- 246 g, X +/- SD; estimated gestational age = 29 +/- 2 weeks) between birth and 30 days of age. The percentage of values lying outside the reference ranges reported recently by Mouzinho et al and previously by Manroe et al were compared. To more accurately assess possible differences in specificity between the two reference ranges, neonates with early-onset group B streptococcal infection (n = 19) were compared with a matched control group (n = 51) using conditional logistic regression. Greater sensitivity was observed using the previous reference ranges of Manroe et al over the entire study period (0 to 720 hours) both for the initial and the second complete blood count (CBC). The previous reference ranges also were more sensitive than the revised ranges for the initial CBC at 0 to 72 and at 73 to 720 hours and for infections attributable to coagulase-negative staphylococci. However, specificity in neonates without group B streptococcal infection was significantly greater with the revised reference ranges compared with those of Manroe et al (initial CBC, 73% vs 45%; serial CBCs, 59% vs 10%). The observed differences in sensitivities may be of limited clinical significance because very low birth weight infants often are begun on antibiotic therapy regardless of laboratory values. However, the striking differences in specificity using the revised reference ranges suggest that these ranges may be clinically useful in determining length of antimicrobial therapy in infants in whom cultures remain sterile.


Quantifying the unknown impact of segmentation uncertainty on image-based simulations.
Image-based simulation, the use of 3D images to calculate physical quantities, relies on image segmentation for geometry creation. However, this process introduces image segmentation uncertainty because different segmentation tools (both manual and machine-learning-based) will each produce a unique and valid segmentation. First, we demonstrate that these variations propagate into the physics simulations, compromising the resulting physics quantities. Second, we propose a general framework for rapidly quantifying segmentation uncertainty. Through the creation and sampling of segmentation uncertainty probability maps, we systematically and objectively create uncertainty distributions of the physics quantities. We show that physics quantity uncertainty distributions can follow a Normal distribution, but, in more complicated physics simulations, the resulting uncertainty distribution can be surprisingly nontrivial. We establish that bounding segmentation uncertainty can fail in these nontrivial situations. While our work does not eliminate segmentation uncertainty, it improves simulation credibility by making visible the previously unrecognized segmentation uncertainty plaguing image-based simulation.


Filterability of membrane bioreactor (MBR) sludge: impacts of polyelectrolytes and mixing with conventional activated sludge.
The main objective of this work was to investigate the filterability of MBR sludge and its mixture with conventional activated sludge (CAS). In addition, the impacts of type and dose of various polyelectrolytes, filter type and sludge properties on the filterability of both MBR and Mixed sludges were determined. Specific cake resistance (SCR) measured by the Buchner funnel filtration test apparatus and the solids content of the resulting sludge cake were used to assess the dewaterability of tested sludges. The type of filter paper used in Buchner tests affected the results of filterability for MBR, CAS and Mixed sludges. SCR values and optimum polyelectrolyte doses increased with increasing MLSS concentrations in the MBR, which suggested that increase in MLSS concentrations accompanied by increases in EPS and SMP concentrations and a shift toward smaller particles caused poorer dewaterability of the MBR sludge. The significant differences observed among the filterability of CAS and MBR sludges suggested that MLSS alone is not a good predictor of sludge dewaterability. Combining CAS and MBR sludges at different proportions generally improved their dewaterability. Combining MBR sludges having typically high MLSS and EPS concentrations with CAS having much lower MLSS concentrations may be an option for full-scale treatment plants experiencing sludge dewaterability problems. Better filterability and higher cake dry solids were achieved with cationic polyelectrolytes compared to anionic and non-ionic ones for all sludge types tested.


Alleviation of oxidative damage in multiple tissues in rats with streptozotocin-induced diabetes by rice bran oil supplementation.
The possibility of 8-hydroxy-2'-deoxyguanosine (8-OHdG) serving as a sensitive biomarker of oxidative DNA damage and oxidative stress was investigated. Reactive oxygen species (ROS) have been reported to be a cause of diabetes induced by chemicals such as streptozotocin (STZ) in experimental animals. In this study, we examined oxidative DNA damage in multiple tissues in rats with STZ-induced diabetes by measuring the levels of 8-OHdG in the liver, kidney, pancreas, brain, and heart. Levels of 8-OHdG in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) were also determined in multiple tissues of rats treated with rice bran oil. Levels were 0.19 +/- 0.07, 0.88 +/- 0.30, 1.97 +/- 0.05, and 9.79 +/- 3.09 (1/10(5) dG) in the liver of nDNA of normal rats, nDNA of STZ-induced diabetic rats, mtDNA of normal rats, and mtDNA of STZ-induced diabetic rats, respectively. Levels of mtDNA of 8-OHdG were 10 times higher than those of nDNA in multiple tissues. Significant reductions in mtDNA 8-OHdG levels were seen in the liver, kidney, and pancreas of diabetic rats treated with rice bran oil compared with diabetic rats without intervention. Our study demonstrated that oxidative mtDNA damage may occur in multiple tissues of STZ-induced diabetics rats. Intervention with rice bran oil treatment may reverse the increase in the frequency of 8-OHdG.


Effects of ivabradine on 6-minute walk test and quality of life in patients with previously implanted CRT-D.
We aimed to evaluate clinical effects of additional heart rate control by ivabradine on life quality score and 6-minute walking test in patients with previously implanted biventricular cardiac resynchronization therapy defibrillator (CRT-D) with ischemic heart failure under regular treatment. Fifteen men and 14 women with a median age of 63 years (range, 48-79 years) were studied. Twenty-one patients were in New York Heart Association class II (8 patients were in class III), CRT-D implanted previously, and with resting heart rates greater than 70 beats per minute with sinus rhythm despite conventional medication. Patients were given 2.5- to 7.5-mg ivabradine orally twice a day, and drug dosage was titrated to decrease the patients' average heart rate to 70 beats per minute. Before and 3 months after ivabradine treatment, all patients underwent extensive clinical, echocardiographic, and laboratory evaluation. Ivabradine treatment produced dose-dependent reductions in heart rate at rest and at peak exercise (91.9 ± 6.3 to 71.7 ± 4.8 and 114.4 ± 7.6 to 96.8 ± 4.8; P = 0.001 and P = 0.001, respectively). There were also significant improvements in life quality score (52.4 ± 9.5 to 37.9±7.8; P = 0.001) and 6-minute walking distance (278.7 ± 85.8 to 373.3 ± 94.0; P = 0.001) of patients. All patients with New York Heart Association class III became class II after 3 months of ivabradine treatment. Heart rate reduction in a short-term period by ivabradine produced significant improvements in exercise capacity and life quality in patients with CRT-D and conventional therapy.


Optimization of Porous Silicon Conditions for DNA-based Biosensing via Reflectometric Interference Spectroscopy.
Substantial effort has been put into designing DNA-based biosensors, which are commonly used to detect presence of known sequences including the quantification of gene expression. Porous silicon (PSi), as a nanostructured base, has been commonly used in the fabrication of optimally transducing biosensors. Given that the function of any PSi-based biosensor is highly dependent on its nanomorphology, we systematically optimized a PSi biosensor based on reflectometric interference spectroscopy (RIS) detecting the high penetrance breast cancer susceptibility gene, BRCA1. In this experimental study, PSi pore sizes on the PSi surface were controlled for optimum filling with DNA oligonucleotides and surface roughness was optimized for obtaining higher resolution RIS patterns. In addition, the influence of two different organic electrolyte mixtures on the formation and morphology of the pores, based on various current densities and etching times on doped p-type silicon, were examined. Moreover, we introduce two cleaning processes which can efficiently remove the undesirable outer parasitic layer created during PSi formation. Results of all the optimization steps were observed by field emission scanning electron microscopy (FE-SEM). DNA sensing reached its optimum when PSi was formed in a two-step process in the ethanol electrolyte accompanied by removal of the parasitic layer in NaOH solution. These optimal conditions, which result in pore sizes of approximately 20 nm as well as a low surface roughness, provide a considerable RIS shift upon complementary sequence hybridization, suggesting efficient detectability. We demonstrate that the optimal conditions identified here makes PSi an attractive solid-phase DNA-based biosensing method and may be used to not only detect full complementary DNA sequences, but it may also be used for detecting point mutations such as single nucleotide substitutions and indels.


Effects of 2 ankle fatigue models on the duration of postural stability dysfunction.
Muscle fatigue is generally categorized in 2 ways: that caused by peripheral weakness (peripheral fatigue) and that caused by a progressive failure of voluntary neural drive (central fatigue). Numerous variables have been studied in conjunction with fatigue protocols, including postural stability, maximum voluntary contraction force, and reaction time. When torque recordings fall below 50% of a maximum voluntary contraction, the muscle is described as fatigued, but whether this value is a good indicator of fatigue has not been studied. To compare the effects of 2 ankle musculature fatigue protocols (30% and 50%) on the duration of postural stability dysfunction. To assess differences between the 30% and 50% fatigue protocols, we calculated a 1 between-groups factor (subjects) and 2 within-groups factors (fatigue, test) analysis of variance. E.J. Nutter Athletic Training Facility. Twenty subjects (10 men, 10 women; age = 21.15 +/- 2.23 years; height = 172.97 +/- 9.86 cm; mass = 70.62 +/- 14.60 kg) volunteered for this study. Subjects had no history of lower extremity injury, vestibular or balance disorders, functional ankle instability, or head injury in the past 6 months. On separate days, subjects performed isokinetic fatiguing contractions of the plantar flexors and dorsiflexors in a 30% protocol (70% decrease in strength) and a 50% protocol (50% decrease in strength). Baseline and postfatigue postural stability scores were determined before and after the isokinetic fatiguing contractions. Plantar-flexion peak-torque measurements were obtained for the 2 fatiguing protocols. Three prefatigue and 12 postfatigue postural stability trials were recorded. Velocities for testing were 60 degrees /s for plantar flexion and 120 degrees /s for dorsiflexion. Sway velocity was significantly greater when the ankle was fatigued to 30% (1.56 degrees /s) than in the 50% condition (1.36 degrees /s). For the 30% protocol, sway was significantly impaired when the pretest condition (1.19 degrees /s) was compared with posttest trial 1 (2.34 degrees /s), trial 2 (2.37 degrees /s), and trial 3 (1.71 degrees /s). For the 50% protocol, sway was significantly impaired when the pretest condition (1.27 degrees /s) was compared with posttest trial 1 (2.02 degrees /s). The 30% fatigue protocol resulted in significantly longer impairment of postural stability than the 50% protocol. Because the 30% protocol resulted in a greater effect but was relatively short-lived (approximately 75 to 90 s), it is more useful for research purposes.


Variability in mobility of children with cerebral palsy.
To examine the variability in mobility of children with cerebral palsy (CP) within classification levels. The subjects were 183 children with CP, ages six to 12 years, at Gross Motor Function Classification System (GMFCS) levels II to IV. Parents reported their child's mobility methods in the home, school, and outdoors/community. Mobility methods were ranked using empirical data and reflect trunk and lower extremity motor control requirements. These ranks were used for Friedman analysis of variance and post-hoc analyses for each GMFCS level. Children within the same GMFCS level exhibited varying degrees of independence in mobility methods, which differed across setting. Children usually performed higher-ranked mobility methods (requiring the most gross motor control) at home, lower-ranked mobility methods at school, and the lowest ranked mobility methods in the outdoors/community. Contextual, environmental, and personal factors may explain these findings. Therapists are encouraged to examine contextual features in everyday settings when planning interventions to improve functional mobility.


Macrosomic newborns of diabetic mothers are associated with increased aortic intima-media thickness and lipid concentrations.
Exposure to diabetes in utero has been established as a significant risk factor for some of components of metabolic syndrome. A few studies have examined relationship between the metabolic syndrome and echocardiographic left ventricular (LV) mass. We aimed to investigate relationship between abdominal aortic intima-media thickness (aIMT), LV mass and lipid profile in macrosomic newborns. Abdominal aIMT was measured in 30 macrosomic neonates of diabetic mothers (group A), 30 macrosomic neonates of healthy mothers (group B) and 30 healthy neonates (group C). Lipid profile and LV mass were determined. Mean aIMT was significantly higher in groups A and B (0.489 +/- 0.015, 0.466 +/- 0.019 mm, respectively) than in controls (0.375 +/- 0.024 mm). Weight-adjusted aIMT in group A was significantly higher than in groups B and C. Macrosomia was associated with increased lipid concentrations. Both LV mass indexed for BSA (body surface area) and birth weight measurements were significantly increased in group A compared with control. Macrosomic neonates of diabetic mothers have significant aIMT and LV mass indexed for BSA and birth weight with lipid alterations. It might play a role in the pathogenesis of atherosclerosis in adult life.


Musculoskeletal Therapies: Acupuncture, Dry Needling, Cupping.
Integrative medicine, including acupuncture, dry needling, and cupping, is being used increasingly in the United States. Evidence regarding their efficacy in the management of musculoskeletal conditions is heterogeneous and subject to several limitations. Despite these limitations, acupuncture consistently has been shown to be more effective than no treatment and is relatively safe. For chronic back pain, it is recommended as a first-line noninvasive therapy. For neck pain, acupuncture provides benefits when it is combined with other treatments. Dry needling is similar to acupuncture and frequently is regarded as a form of acupuncture. Evidence similar to that for acupuncture supports the use of dry needling for patients with localized musculoskeletal pain conditions. The effects of these procedures do not appear to persist beyond 6 months. Data on maintenance treatments are sparse. Cupping refers to the application of suction on tender musculotendinous areas via various devices. It is theorized to help relieve inflammation. Wet cupping appears to decrease low back and neck pain. Patients should be referred to appropriately credentialed clinicians. Health insurance companies may not provide coverage for these therapies.


Future perspectives of prostate cancer therapy.
We summarize several recent laboratory advances to tackle the problem of tumor-stroma-immune cell microenvironment interaction with the hope of developing and advancing new concepts and therapeutic strategies for prostate cancer therapy by improving bone and soft tissue metastases in prostate cancer patients. Given the emerging enthusiasm for immunotherapy in prostate cancer due to (I) improved understanding of the role of immune cells in the tumor microenvironment, (II) approval by the FDA of an immunotherapeutic drug to treat prostate cancer, and (III) recognition of immunotherapy as a novel approach to treat solid tumors by the Nobel Prize Committee (for discovery of dendritic cells that are used in immunotherapy), the field of tumor immunology is poised for growth in the next decade with the hope of developing new immunomodulatory drugs which will compliment and perhaps eventually replace traditional chemotherapeutic drugs. In this article, we provide a timely review of recent advances in the field of immunotherapy for prostate cancer, lessons learned from successes and failures, the contributory factors in the tumor microenvironment that could be rendered hostile to cancer cells, an exciting area of future research.


Insights into the genome structure and copy-number variation of Eimeria tenella.
Eimeria is a genus of parasites in the same phylum (Apicomplexa) as human parasites such as Toxoplasma, Cryptosporidium and the malaria parasite Plasmodium. As an apicomplexan whose life-cycle involves a single host, Eimeria is a convenient model for understanding this group of organisms. Although the genomes of the Apicomplexa are diverse, that of Eimeria is unique in being composed of large alternating blocks of sequence with very different characteristics - an arrangement seen in no other organism. This arrangement has impeded efforts to fully sequence the genome of Eimeria, which remains the last of the major apicomplexans to be fully analyzed. In order to increase the value of the genome sequence data and aid in the effort to gain a better understanding of the Eimeria tenella genome, we constructed a whole genome map for the parasite. A total of 1245 contigs representing 70.0% of the whole genome assembly sequences (Wellcome Trust Sanger Institute) were selected and subjected to marker selection. Subsequently, 2482 HAPPY markers were developed and typed. Of these, 795 were considered as usable markers, and utilized in the construction of a HAPPY map. Markers developed from chromosomally-assigned genes were then integrated into the HAPPY map and this aided the assignment of a number of linkage groups to their respective chromosomes. BAC-end sequences and contigs from whole genome sequencing were also integrated to improve and validate the HAPPY map. This resulted in an integrated HAPPY map consisting of 60 linkage groups that covers approximately half of the estimated 60 Mb genome. Further analysis suggests that the segmental organization first seen in Chromosome 1 is present throughout the genome, with repeat-poor (P) regions alternating with repeat-rich (R) regions. Evidence of copy-number variation between strains was also uncovered. This paper describes the application of a whole genome mapping method to improve the assembly of the genome of E. tenella from shotgun data, and to help reveal its overall structure. A preliminary assessment of copy-number variation (extra or missing copies of genomic segments) between strains of E. tenella was also carried out. The emerging picture is of a very unusual genome architecture displaying inter-strain copy-number variation. We suggest that these features may be related to the known ability of this parasite to rapidly develop drug resistance.